Defective mucociliary clearance (MCC) is central to the pathogenesis of prevalent lung diseases, including COPD/chronic bronchitis, cystic fibrosis, bronchiectasis, and ventilator associated pneumonia. In each instance, defective MCC leads to the development of lung infection and inflammatory damage. Our long- term goals are to reach an indepth understanding of MCC in health and disease and to develop effective therapies that support and/or restore MCC in patients with these diseases. In the proposed project, we will explore the effects of available agents from three different therapeutic classes on actual measurements of mucociliary and cough clearance in patients with the chronic bronchitis phenotype of COPD. The selected therapeutic activities include an osmotic hydrator (7% NaCI; hypertonic saline), a detergent (lucinactant; KL4 surfactant), and an epithelial sodium channel blocker (PS-552). New delivery methods are also being tested in studies of HS and lucinactant. MCC measurements will be used to characterize both the acute effect (1 hour after dosing) and the durability of this effect through 4 hours. In the case of hypertonic saline (HS) (Aim 1) and combination therapy with PS-552 plus HS (Aim 4), the sustained effect on MCC (12 hours) after 2 weeks of dosing will be tested. In addition, a panel of novel biomarkers that report on the activities of these therapies will be used to better understand observed treatment effects. These novel biomarkers may ultimately prove to be useful in the conduct of larger clinical studies of similar agents in the future as well. Finally, the airway surface pharmacokinetics of lucinactant and PS-552 will be characterized using exhaled breath condensate collections and mass spectroscopy. If validated, these data will help us evaluate dose- response relationships we measure in humans, and will allow us to make direct comparisons to in vitro and animal studies performed in the accompanying projects and cores. In concert with the other Projects and Cores in this tPPG, we anticipate that these proposed studies will significantly advance us toward new treatment strategies for COPD. RELEVANCE (See instructions): COPD affects more than 14 million Americans, and is the 3rd leading cause of death. Based on our experience in cystic fibrosis, therapies that restore MC are expected to significantly reduce the frequency of pulmonary exacerbations, which in turn are major determinants of disease progression, quality of life, and associated healthcare costs. If successful, our proposed treatment paradigms may have a major impact on the way that COPD and related disorders are treated.